Biodistribution and radiation dosimetry of the dopamine transporter ligand.

UNLABELLED: 18F-labeled 2 beta-carbomethoxy-3beta-(4-chlorophenyl)-8-(-2-fluoroethyl)nortropane ([18F]FECNT) is a recently developed dopamine transporter ligand with potential applications in patients with Parkinson's disease and cocaine addiction. METHODS: Estimates of the effective dose equivalent and doses for specific organs were made using biodistribution data from 16 Sprague-Dawley rats and nine rhesus monkeys. PET images from two rhesus monkeys were used to calculate the residence time for the basal ganglia. The computer program MIRDOSE3 was used to calculate the dosimetry according to the methodology recommended by MIRD. RESULTS: The basal ganglia were the targeted tissues receiving the highest dose, 0.11 mGy/MBq (0.39 rad/mCi). The effective dose equivalent was 0.018 mSv/MBq (0.065 rem/mCi), and the effective dose was 0.016 mSv/MBq (0.058 rem/mCi). CONCLUSION: Our data show that a 185-MBq (5-mCi) injection of [18F]FECNT leads to an estimated effective dose of 3 mSv (0.3 rem) and an estimated dose to the target organ or tissue of 19.4 mGy (1.93 rad).

SPECT imaging with the D(4) receptor antagonist L-750,667 in nonhuman primate brain.

The suitability of an (123)I-labeled form of the putative D(4) receptor ligand L750,667 as a radiotracer for single photon emission computed tomography imaging was assessed in nonhuman primates. [(123)I]L750,667, labeled by iododestannylation, was administered to baboons in bolus and bolus plus constant infusion paradigms and imaged for 6 h. Total [(123)I]L750,667 brain uptake peaked (2.3% injected dose) at 15 min postinjection. [(123)I]L750,667 uptake was observed in all brain regions measured including diencephalon, brainstem, basal ganglia, cingulate cortex, and cerebellum, and slightly lower levels were noted in the frontal, parietal, temporoinsular, and occipital cortices. Administration of the D(4) receptor antagonist NGD 94-1 (2 mg/kg) did not displace radioactivity from any of the brain regions examined. Thus, while L750,667 is selective for the D(4) receptor in vitro, because brain [(123)I]L750,667 uptake was not displaced by NGD 94-1 at receptor saturating doses, [(123)I]L750,667 does not appear to be a suitable radiotracer for in vivo imaging of the D(4) receptor.

Radiopharmaceuticals for lymphoscintigraphy: including dosimetry and radiation considerations.

The recognition of the importance of lymphoscintigraphy for identification of the sentinel lymph nodes in melanoma and breast cancer plays a significant role in the clinical management of these patients. The widespread clinical acceptance of this technique and the lack of an agreement on which radiopharmaceutical agent has the most ideal properties has resulted in a wide variety of agents being used clinically with other agents under investigation or development. This article reviews some of the physical properties that a radiopharmaceutical agent should possess and discusses in depth commonly used agents and lists some agents under development. This article also discusses the dosimetry and biological effects various radiopharmaceutical agents have for lymphoscintigraphy in melanoma and breast cancer patients. In view of the lack of a consensus agreement on which radiopharmaceutical agent will provide the optimal clinical information this article will provide an overview of potentially useful radiopharmaceutical agents and radiation dosimetry considerations.

Effect of protein binding on renal extraction of 131I-OIH and 99mTc-labeled tubular agents.

UNLABELLED: The clearance of 99mTc-mercaptoacetyltriglycine (MAG3) is less than the clearances of o-131I-iodohippurate (OIH) and 99mTc-labeled DD- and LL-ethylenedicysteine (EC). This difference could be associated with the lower affinity of MAG3 for the tubular transport receptor, but MAG3 is more highly protein bound than OIH and the EC isomers; protein binding could also be an important factor governing tubular extraction. To separate the effects of protein binding from tubular receptor affinity, the extraction fractions (EFs) of MAG3, OIH, and the DD, LL, and DL isomers of 99mTc-EC were measured in an isolated perfused rat kidney model using a protein-free perfusate and perfusates containing bovine serum albumin. METHODS: The right kidney was removed from the rat and perfused with modified Krebs-Henseleit buffers containing 7.5 or 2.5 g/dL bovine serum albumin or a protein-free perfusate. OIH was coinjected into the renal artery with each of the 99mTc-tracers. Protein binding was measured in each of the perfusates, and the venous outflow was collected to determine the EF. RESULTS: The protein binding of MAG3 in the albumin perfusates ranged from 87% to 95%, significantly higher than the 20%-34% range of protein binding observed with the three EC complexes (P < 0.05). In the 2.5 g/dL albumin perfusate, the EF of MAG3 was 44%, significantly less than the 57%-77% EF of the three EC complexes; in the 7.5 g/dL perfusate, the MAG3 EF fell to 18% versus 39%-45% for the EC complexes (P < 0.05). However, in the protein-free perfusate, the EF of MAG3 was 64%, equal to or higher than the 46%-62% EF of the three EC complexes. CONCLUSION: Protein binding modulates the tubular extraction of renal tracers. Protein binding and receptor affinity must be considered in the design of future renal radiopharmaceuticals as well as radiopharmaceuticals targeting other receptors.

Synthesis and evaluation of [18F]1-amino-3-fluorocyclobutane-1-carboxylic acid to image brain tumors.

UNLABELLED: We have developed a new tumor-avid amino acid, 1-amino-3-fluorocyclobutane-1-carboxylic acid (FACBC), labeled with 18F for nuclear medicine imaging. METHODS: [18F]FACBC was prepared with high specific activity (no carrier added [NCA]) and was evaluated for its potential in tumor localization. A comparative study was performed for [18F]FACBC and [18F]2-fluorodeoxyglucose (FDG) in which the uptake of each agent in 9L gliosarcoma (implanted intracerebrally in Fisher 344 rats) was measured. In addition, the first human PET study of [18F]FACBC was performed on a patient with residual glioblastoma multiforme. Quantitative brain images of the patient were obtained by using a Siemens 921 47-slice PET imaging system. RESULTS: In the rat brain, the initial level of radioactivity accumulation after injection of [18F]FACBC was low (0.11 percentage injected dose per gram [%ID/g]) at 5 min and increased slightly to 0.26 %ID/g at 60 min. The tumor uptake exhibited a maximum at 60 min (1.72 %ID/g), resulting in a tumor-to-brain ratio increase of 5.58 at 5 min to 6.61 at 60 min. In the patient, the uptake of [18F]FACBC in the tumor exhibited a maximum concentration of 146 nCi/mL at 35 min after injection. The uptake of radioactivity in the normal brain tissue was low, 21 nCi/mL at 15 min after injection, and gradually increased to 29 nCi/mL at 60 min after injection. The ratio of tumor to normal tissue was 6 at 20 min after injection. The [18F]FACBC PET scan showed intense uptake in the left frontal region of the brain. CONCLUSION: The amino acid FACBC can be radiofluorinated for clinical use. [18F]FACBC is a potential PET tracer for tumor imaging.

Lymphoscintigraphic identification of sentinel lymph nodes: clinical evaluation of 0.22-micron filtration of Tc-99m sulfur colloid.

PURPOSE: To evaluate the use of 0.22-micron filtration of technetium-99m sulfur colloid particles in the optimization of lymphoscintigraphy. MATERIALS AND METHODS: Forty-one consecutive lymphoscintigraphic studies obtained with 0.22-micron filtration of Tc-99m sulfur colloid in 41 patients (26 men, 15 women; average age, 55.4 years) and 41 consecutive studies obtained with 5.0-micron filtration in 41 patients (20 men, 21 women; average age, 54.5 years) were retrospectively, randomly reviewed. Studies were evaluated for lymphatic channel depiction and sentinel lymph node depiction. Studies included immediate flow images (obtained at 10 seconds per frame) and multiview static images obtained up to 2 hours after intradermal Tc-99m sulfur colloid injection. RESULTS: The number of drainage beds visualized was 52 with 5.0-micron filtration and 51 with 0.22-micron filtration (P = .570). The number of lymphatic channels visualized was 45 with 5.0-micron filtration and 75 with 0.22-micron filtration (P = .006). The number of lymph nodes visualized was 102 with 5.0-micron filtration and 123 with 0.22-micron filtration (P = .123). The number of studies judged as optimal (i.e., depicted lymphatic channels leading to sentinel nodes) was 10 with 5.0-micron filtration and 19 with 0.22-micron filtration (P = .038). The number of studies with depicted lymph nodes but no depicted lymphatic channel was 15 with 5.0-micron filtration and six with 0.22-micron filtration (P = .023). CONCLUSION: The use of 0.22-micron filtration in the preparation of Tc-99m sulfur colloid substantially improves study quality and increases the diagnostic certainty in the identification of sentinel lymph nodes.

Multicenter trial validation of a camera-based method to measure Tc-99m mercaptoacetyltriglycine, or Tc-99m MAG3, clearance.

PURPOSE: To evaluate an improved camera-based method for calculating the clearance of technetium-99m mercaptoacetyltriglycine (MAG3) in a multicenter trial. MATERIALS AND METHODS: Tc-99m MAG3 scintigraphy was performed in 49 patients at three sites in the United States and Canada. The percentage of the injected dose of Tc-99m MAG3 in the kidney at 1-2, 1.0-2.5, and 2-3 minutes after injection was correlated with the plasma-based Tc-99m MAG3 clearances. The data were combined with the results obtained in 20 additional patients in a previously published pilot study. RESULTS: Regression models correlating the plasma-based Tc-99m MAG3 clearance with the percentage uptake in the kidney for each time interval were developed; there was no statistically significant difference among sites in the regression equations. Correction for body surface area statistically significantly (P < .005) improved the correlation coefficient for each time interval. For the 1.0-2.5-minute interval, the body surface area-corrected correlation coefficient for the four combined sites was .87, and it improved to .93 when one outlier was omitted from the analysis. Similar results were obtained with the other time intervals. Independent processing by two observers showed no clinically important differences in the percentage dose in the kidney or in relative function. CONCLUSION: An improved camera-based method to calculate the clearance of Tc-99m MAG3 was validated in a multicenter trial.

Fluorine-18-FPCT: a PET radiotracer for imaging dopamine transporters.

UNLABELLED: Fluorine-18-labeled 2 beta-carbomethoxy-3 beta-(4-chlorophenyl)-8-[-3-fluoropropyl) nortropane (FPCT) has been synthesized as a new dopamine transporter imaging agent. METHODS: Fluorine-18 was introduced into 2 beta-carbomethoxy-3 beta-(4-chlorophenyl)-8-[-3-fluoropropyl) nortropane by preparation of 1-[18F]fluoro-3-iodopropane followed by alkylation of 2 beta-carbomethoxy-3 beta-(4-chlorophenyl)nortropane. RESULTS: Tissue distribution studies in rats with [18F]FPCT showed high striatal uptake (0.70% dose/g at 60 min; 0.38% dose/g at 120 min) and good striatal-to-cerebellum ratios (5.5 at 60 min; 6.2 at 120 min). Imaging studies in rhesus monkeys (n = 2) with [18F]FPCT showed high uptake and retention in the putamen (P) (P = 0.03%-0.12% dose/g; at 115 min) and good putamen-to-cerebellum ratios of 3.40-3.43 at 115 min. Plasma metabolites were analyzed in rhesus monkeys (n = 2) by ether extraction and HPLC. The radioactivity in the ether-extractable fraction displayed a single peak that corresponded on HPLC to unmetabolized authentic FPCT. CONCLUSION: These results suggest that [18F]FPCT is an excellent candidate for PET imaging of dopamine transporters.

Lymphoscintigraphy, the sentinel node concept, and the intraoperative gamma probe in melanoma, breast cancer, and other potential cancers.

There is a resurgence of interest in lymphoscintigraphy because of attention to the sentinel node concept and the availability of the surgical gamma probe that can be used in the operating room to localize radiolabeled sentinel nodes. Conventional surgical management of melanoma has been altered for intermediate thickness tumors such that lymph node dissection is performed for a lymph node bed only if the sentinel node is tumor positive on histological exam after gamma probe-guided excision. This approach is cost effective, saving about 80% of these patients (sentinel node tumor negative) the cost and morbidity of unnecessary "elective lymph node dissection." In addition, a biopsy can be performed on all lymph node beds that receive lymphatic drainage from the tumor site thereby improving staging and perhaps survival by providing the most appropriate therapy. Substantial work has been done to develop optimum imaging techniques and the best radiopharmaceutical preparation to achieve accurate, reproducible lymphatic drainage images. Our methodology includes the following intradermal injections of a technetium 99m sulfur colloid (modified preparation) are followed by dynamic imaging (10 seconds per frame); static imaging up to 30 minutes and late imaging at 1 to 2 hours. Images show lymphatic channels that lead to sentinel nodes in 1, 2, 3, or more anatomic locations. Surgical management is altered to include sampling sentinel nodes of nodal beds, many of which would not have been sampled by previous conventional surgical estimates of lymphatic drainage. While clinical success of lymphoscintigraphy and intraoperative probe localization of the sentinel node in melanoma is evident, use of lymphoscintigraphy and the sentinel node concept in breast cancer is investigative, but promising. The radiopharmaceutical is injected around the tumor in the breast followed by imaging to delineate lymphatic drainage to the sentinel node(s). Optimum methodologies for radiopharmaceutical, volume and/or activity of injectate, and imaging have yet to be determined. Breast lymphatic drainage can be to axilla, internal mammary, and/or supraclavicular nodes in any combination.

Technetium-99m-sulfur colloid for lymphoscintigraphy: effects of preparation parameters.

UNLABELLED: There has been a resurgence in the use of lymphoscintigraphy for the external detection of lymph nodes for metastatic melanoma and breast tumors. Technetium-99m-antimony trisulfide colloid was the radiopharmaceutical developed for this procedure and was found to have a narrow distribution of small particles, 0.003-0.03 microns, but it was never approved by the FDA. Technetium-99m-sulfur colloid also forms particles and this article reports on the effects different preparation parameters have on its particle size distribution and stability. METHODS: Four groups of kits were evaluated, kits which utilized: (a) a reduced heating protocol with a new 99mTc-elution, (b) a reduced heating protocol with an old 99mTc-elution, (c) a prolonged heating protocol with a new 99mTc-elution and (d) a prolonged heating protocol with an old 99mTc-elution. The particle size distribution and the stability of the different 99mTc-sulfur colloid kit preparations were evaluated over 6 hr utilizing polycarbonate filters ranging from 0.03 to 10 microns. RESULTS: In vitro studies demonstrated no significant change in the particle size distribution over a 6-hr period and all 99mTc-sulfur colloid preparations had a bimodal particle size distribution pattern. Importantly, heating the kit for shorter periods of times utilizing [99mTc]pertechnetate, which had a longer ingrowth of [99mTc]pertechnetate, produced a formulation which had the largest percentage of particles smaller than 0.03 microns. CONCLUSION: In our clinical setting, 99mTc-sulfur colloid prepared with the reduced heating protocol and utilizing [99mTc]pertechnetate, which has the highest ingrowth of [99mTc]pertechnetate has proved to be an excellent agent for lymphoscintigraphy studies. This preparation has demonstrated rapid movement of the particles from the primary site to the lymph nodes in over 97% (106/109) of the patients we have studied.